Activation of p75NTR by proBDNF facilitates hippocampal long-term depression

Pro- and mature brain-derived neurotrophic factor (BDNF) activate two distinct receptors: p75 neurotrophin receptor (p75 NTR ) and TrkB. Mature BDNF facilitates hippocampal synaptic potentiation through TrkB. Here we report that proBDNF, by activating p75 NTR , facilitates hippocampal long-term depression (LTD). Electron microscopy showed that p75 NTR localized in dendritic spines, in addition to afferent terminals, of CA1 neurons. Deletion of p75 NTR in mice selectively impaired the NMDA receptor–dependent LTD, without affecting other forms of synaptic plasticity. p75 NTR−/− mice also showed a decrease in the expression of NR2B, an NMDA receptor subunit uniquely involved in LTD. Activation of p75 NTR by proBDNF enhanced NR2B-dependent LTD and NR2B-mediated synaptic currents. These results show a crucial role for proBDNF-p75 NTR signaling in LTD and its potential mechanism, and together with the finding that mature BDNF promotes synaptic potentiation, suggest a bidirectional regulation of synaptic plasticity by proBDNF and mature BDNF.